Anti-virally active pyridazinamines

ABSTRACT

Anti-virally active pyridazinamines, compositions containing the same and methods of treating viral diseases in warm-blooded animals.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 702,772, filed onFeb. 15, 1985, now U.S. Pat. No. 5,001,125 which was acontinuation-in-part of application Ser. No. 593,444, filed on Mar. 26,1984, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with anti-viral agents,pharmaceutical compositions containing these agents and methods oftreating warm-blooded animals suffering from viral diseases.

Viral infections are generally taught to be responsible for a number ofdiseases of various nature such as, for example, rabies, hepatitis,herpes, common cold, etc. . . . More particularly, the latt disease iswidely spread throughout the world and is a major cause of sickness andabsence from work. An agent capable of treating said disease would be agreat benefit to mankind and certainly be of great economic importance.

Up until now no such agents are available and there exists noestablished chemotherapeutic agent against the said disease.

The present invention discloses the useful anti-viral properties of anumber of pyridazine derivatives and their use in the treatment of viraldiseases. Some of the pyridazinamines of the present invention are knownin the art as intermediates for the synthesis of other useful compoundsor as compounds having certain pharmacological properties. Thesecompounds and a number of structurally closely related compounds can befound in the following references.

In J. Med. Chem. 24, 59-63 (1981) there are described a number of1H-imidazolyl-pyridazines, while in European Patent Number 55,583, U.S.Pat. Nos. 4,110,450, 4,104,385 and 2,985,657 a number of piperazinyl,pyrrolidinyl and piperidinyl substituted pyridazines are described asintermediates. In European Patent Number 9,6553-chloro-6-[4-(2-methoxyphenyl)-1-piperazinyl]pyridazine and1-chloro-4-(4-hydroxypiperidino)phtalazine are also described asintermediates. Moreover a number of substituted 1-piperzinyl-pyridazinesare described in J. Med. Chem. 6, 541-4 (1963), in ibid. 8, 104-107(1965) and ibid. 15, 295-301 (1972) as compounds having adrenolytic,anti-histaminic or analgesic activity.

The compounds of the present invention differ from the cited prior-artcompounds by the specific substitution on the pyridazine moiety andparticularly by their useful anti-viral properties.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention, there are provided anti-virallyactive pyridazinamines which may structurally be represented by theformula ##STR1## the pharmaceutically acceptable acid-addition saltsand/or possible stereochemically isomeric forms and/or possibletautomeric forms thereof, wherein

R¹ is a member selected from the group consisting of hydrogen, halo,1H-imidazol-1-yl, lower alkyloxy, aryloxy, aryllower alkyloxy, loweralkylthio, arylthio, hydroxy, mercapto, amino, lower alkylsulfinyl,lower alkylsulfonyl, cyano, lower alkyloxycarbonyl, lower alkylcarbonyl,and lower alkyl;

R² and R³ are, each independently, members selected from the groupconsisting of hydrogen and lower alkyl, or R² and R³ combined may form abivalent radical of formula --CH═CH--CH═CH--;

A is a bivalent radical of formula: ##STR2## wherein one of the hydrogenatoms within the radical C_(m) H_(2m), C_(m-1) H₂(m-1) or C_(n) H_(2n)may be replaced by lower alkyl or aryl;

m and n are, each independently, integers of from 1 to 4 inclusive, thesum of m and n being 3, 4 or 5;

R⁴ is a member selected from the group consisting of hydrogen; loweralkyl; aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl;lower alkyloxycarbonyl; aryllower alkyl; diaryllower alkyl; phenyl beingsubstituted with arylcarbonyl; pyridinyl, being optionally substitutedwith cyano or lower alkyl; cyclohexyl and cyclohexenyl both beingoptionally substituted with up to two substituents independentlyselected from the group consisting of cyano and aryl;

R⁵ is hydrogen; lower alkyl; aryl; hydroxy; lower alkyloxy; aryloxy;lower alkyloxy being substituted with morpholine, pyrrolidine orpiperidine; amino; (lower alkyloxycarbonyl)amino; arylamino;(aryl)(lower alkyl)amino; (aryllower alkyl)amino; (arylloweralkenyl)amino; (aryllower alkenyl)(lower alkyl)amino; arylcarbonyloxy;

R⁶ is hydrogen; aryl; lower alkyl; (lower alkylcarbonyl amino)loweralkyl, aryllower alkyl; arylcarbonyllower alkyl; aminocarbonyl;arylcarbonyl; arylaminocarbonyl; (aryllower alkyl)carbonyl, loweralkyloxcarbonyl; indolyl; pyridinyl;

R⁷ and R⁸ are, each independently, members selected from the groupconsisting of hydrogen, lower alkyl, aryl, aryllower alkyl andpyridinyl; wherein aryl is phenyl, being optionally substituted with upto 3 substituents, each independently selected from the group consistingof halo, lower alkyl, trifluoromethyl, nitro, amino, lower alkyloxy,hydroxy and lower alkyloxycarbonyl; thienyl; and napthalenyl.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; "lower alkyl" is meant to include straight andbranched saturated hydrocarbon radicals, having from 1 to 6 carbon atom,such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl,propyl, butyl, pentyl, hexyl and the like; "lower alkenyl" refers toalkenyl radicals having from 2 to about 6 carbon atoms, such as, forexample, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like.

The compounds of formula (I) can generally be prepared by N-alkylatingan amine of formula (II) with a reagent of formula (III) followingart-known N-alkylating procedures. ##STR3##

In (III) W represents an appropriate reactive leaving group such as, forexample, halo, i.e. fluoro, chloro, bromo or iodo, or a sulfonyloxygroup, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy a loweralkyloxy or lower alkylthio group.

The alkylation reactions can conveniently be conducted in an inertorganic solvent such as, for example, an aromatic hydrocarbon, e.g.,benzene, methylbenzene, dimethylbenzene, and the like; a lower alkanol,e.g., methanol, ethanol, 1-butanol and the like; a ketone, e.g.,2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.,1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; a dipolaraprotic solvent such as, for example, N,N-dimethylformamide (DMF);N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); nitrobenzene;1-methyl-2-pyrrolidinone; and the like. The addition of an appropriatebase such as, for example, an alkali metal carbonate or hydrogencarbonate, sodium hydride or an organic base such as, for example,N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine may be utilizedto pick up the acid which is liberated during the course of thereaction. In some circumstances the addition of an iodide salt,preferably an alkali metal iodide, is appropriate. The alkylationreactions can also be conducted by mixing and/or melting the reactantstogether, optionally in the presence of the bases mentioned hereinabove.Somewhat elevated temperatures may be used to enhance the rate of thereaction.

The compounds of formula (I) can also be converted into each other by anappropriate functional groupstransformation reaction. For example, thecompounds of formula (I), wherein A is a radical of formula (b) whereinR⁴ is a hydrogen radical, said compounds being represented by theformula (I-a), may be alkylated or acylated with a reagent of formula(IV) following the procedures described hereinabove for the preparationof (I) starting from (II) and (III), thus obtaining a compound offormula (I-b). ##STR4## In (IV), W has the previously defined meaning,and R^(4-a) is as R⁴, provided that it is not hydrogen.

The compounds of formula (I), wherein A is a radical of formula (b),wherein R⁴ is lower alkyl, aryllower alkyl, diaryllower alkyl,cyclohexyl or cyclohexenyl, said R⁴ being represented by R^(4-b) andsaid compounds by the formula (I-c), may be prepared by reductivelyN-alkylating a compound of formula (I-a) with an appropriatecarbonyl-compound of formula (R^(4-b-1))═C═O, said (R^(4-b-1))═C═O beinga compound of formula R^(4-b) --H, wherein a --CH₂ -radical is oxidatedto a carbonyl radical. ##STR5## Said reductive N-alkylation reaction mayconveniently be carried out by catalytically hydrogenating a stirred andheated mixture of the reactants in a suitable reaction-inert organicsolvent according to art-known catalytic hydrogenating procedures. Thereaction mixture may be stirred and/or heated in order to enhance thereaction rate. Suitable solvents are, for example, water; loweralkanols, e.g. methanol, ethanol, 2-propanol and the like; cyclicethers, e.g. 1,4-dioxane and the like; halogenated hydrocarbons, e.g.trichloromethane and the like; N,N-dimethylformamide; dimethyl sulfoxideand the like; or a mixture of 2 or more of such solvents. The term"art-known catalytic hydrogenating procedures" means that the reactionis carried out under hydrogen atmosphere and in the presence of anappropriate catalyst such as, for example, palladium-on-charcoal,platinum-on-charcoal and the like. In order to prevent the undesiredfurther hydrogenation of certain functional groups in the reactants andthe reaction products it may be advantageous to add an appropriatecatalyst-poison to the reaction mixture, e.g., thiophene and the like.

The compounds of formula (I), wherein A is a radical of formula (b),wherein R⁴ is hydrogen can be converted into the corresponding compoundswherein R⁴ is an optionally substituted 2-cyclohexenyl radical, byreacting the former compounds with an appropriate cyclohexanonederivative in the presence of a suitable solvent such as, for example, ahydrocarbon, e.g. benzene, methylbenzene and the like. In some cases itmay be advantageous to supplement the reaction mixture with anappropriate acid, e.g. 4-methylsulfonic acid and the like.

Or, conversely, the compounds of formula (I), wherein A is a radical offormula (b) wherein R⁴ is lower alkyloxycarbonyl or lower alkylcarbonylmay be deacylated following art-known procedures, e.g. by reacting thestarting compounds with an appropriate acidic or basic solution.

Similarly, the compounds of formula (I) wherein A is a radical offormula (c) wherein R⁵ is (lower alkyloxycarbonyl) amino may beconverted into the corresponding amino-compounds.

The compounds of formula (I) wherein A is a radical of formula (c)wherein R⁵ is hydroxy can be converted into the corresponding compoundsof formula (I) wherein A is a radical of formula (d) by an eliminationreaction. This can be accomplished by reacting the former compounds witha suitable acidic solution preferably at higher temperatures. Suitableacidic solutions contain one or more acids such as sulfuric,hydrochloric, acetic and the like acids in admixture with water and/oran organic solvent, such as methanol, ethanol and the like.

Or the starting hydroxy containing compounds can be reacted with anappropriate deshydratating agent such as, for example, phosphorylchloride, thionyl chloride, phosphor trichloride, preferably in thepresence of a suitable solvent such as, for example, pyridine,N,N-dimethylformamide (DMF) and the like.

The compounds of formula (I) containing a cyclohexenyl radical may beconverted into the corresponding cyclohexyl containing compounds by anappropriate reduction procedure, e.g. by reacting the former compoundswith a metal hydride, e.g. sodium borohydride, in a suitable solvent,e.g. an alkanol such as methanol and the like, optionally in thepresence of a base, e.g. sodium methoxide and the like.

The compounds of formula (I), wherein R¹ is halo may be converted intothe corresponding compounds wherein R¹ is lower alkyloxy, aryloxy,aryllower alkyloxy, lower alkylthio or arylthio by reacting the saidhalo containing compounds with an appropriate aromatic or aliphaticalcohol or mercaptane. The said reaction may be conducted in anappropriate solvent such as, for example a ketone, e.g. 2-propanone,DMF, DMA and the like solvents. The addition of a suitable base such as,for example, an alkali metal hydride, e.g. sodium hydride, an alkalimetal carbonate, e.g. sodium carbonate may be used to enhance the rateof the reaction. Alternatively, the starting halo compounds may bereacted with an appropriate alkali metal alkoxide, aryloxide or (arylsubstituted)alkoxide in a suitable solvent, preferably in thecorresponding alcohol, thus preparing the desired compounds of formula(I) wherein R¹ is lower alkyloxy, aryloxy and aryllower alkyloxy.

The compounds of formula (I) wherein R¹ is arylmethyloxy may beconverted into the corresponding hydroxy compounds following art-knownprocedures for the removal of the arylmethyl group, e.g. by reacting thestarting compounds with an acidic solution or with hydrogen in thepresence of an appropriate catalyst in a suitable solvent.

The compounds of formula (I), wherein R¹ is halo may be converted intothe corresponding compounds wherein R¹ is hydrogen, following art-knownhydrogenolysis procedures, i.e. by heating the starting compounds in asuitable solvent under hydrogen atmosphere in the presence of anappropriate catalyst, e.g. palladium-on-charcoal and the like catalysts.

The compounds of formula (I), wherein R¹ is halo may further beconverted into the corresponding mercapto containing compounds byreacting the former compounds with hydrogen sulfide or a reagent capableof generating hydrogen sulfide, e.g. thiourea in the presence of a base.

The compounds of formula (I) wherein R¹ is lower alkyloxycarbonyl may beconverted into the corresponding lower alkylcarbonyl compounds byreacting the starting compounds with an appropriate ester in thepresence of an alkali metal in a suitable alcohol.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxicacid-addition salt forms by treatment with appropriate acids, such as,for example, inorganic acids, such as hydrohalic acid, e.g.hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid,phosphoric acid and the like; or organic acids, such as, for example,acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

A number of intermediates and starting materials in the foregoingpreparations are known compounds which may be prepared according toart-known methodologies as described, for example, in U.S. Pat. Nos.2,997,472; 2,979,507; 2,997,474 and 3,002,976.

The intermediates of formula (II), wherein A is a radical of formula(b), wherein R⁴ is other than hydrogen, said R⁴ being represented byR^(4-a) and said intermediates by the formula (II-a), may be prepared byalkylating an amine of formula (V) with a reagent of formula (IV), thusyielding an intermediate of formula (VI), and subsequently eliminatingthe group P. In (V) and (VI) P is an appropriate protective group suchas, for example, lower alkyloxycarbonyl, arylmethoxycarbonyl,arylmethyl, arylmethyl, arylsulfonyl and the like. The elimination of Pin (VI) may generally be carried out following art-known procedures suchas, for example, by hydrolysis in alkaline or acidic medium. ##STR6##

The intermediates of formula (VI) may also be prepared by N-alkylatingan amine of formula (VII) with a reagent of formula (VIII), followingart-known N-alkylating procedures. ##STR7## The reaction of (IV) with(V) and of (VII) with (VIII) may be conducted following the sameprocedures described hereinabove for the preparation of (I) startingfrom (II) and (III).

The intermediates of formula (II), wherein A is a radical of formula(c), wherein R⁶ is hydrogen and R⁵ is a radical of formula --NR⁹ R¹⁰,said --NR⁹ R¹⁰ being arylamino, (aryl)(lower alkyl)amino, (arylloweralkyl)amino, (aryllower alkenyl) (lower alkyl)amino, (arylloweralkenyl)amino, said intermediates being represented by the formula(II-b), can conveniently be prepared by reductively N-alkylating aketone of formula (IX) with an amine of formula (X), thus yielding anintermediate of formula (XI), and subsequently eliminating theprotective group P. In (IX) and (XI), P has the previously describedmeaning. ##STR8## The said reductive amination may conveniently becarried out by catalytically hydrogenating a mixture of the reactants ina suitable reaction-inert medium, according to art-known procedures.

The intermediates of formula (II), wherein A is a bivalent radical offormula (c) wherein R⁵ is hydroxy and R⁶ is aryl, lower alkyl orsubstituted lower alkyl can be prepared by reacting (IX) with anappropriate Grignard reagent in a suitable solvent. The thus obtainedhydroxy containing intermediates may be deprotected or further reactedwith a suitable acidic solution in order to eliminate a water moleculeand subsequently be deprotected thus preparing intermediates of formula(II) wherein A is a radical of formula (d).

The compounds of formula (I) show anti-viral activity and areparticularly attractive due to their favourable therapeutic index,resulting from an acceptable low degree of cell toxicity, combined witha desirable anti-viral activity at low doses.

The useful anti-viral properties of the compounds of formula (I) aredemonstrated in the following test procedure.

Rhinovirus Cythopatic Effect Test

Rhinovirus-sensitive Hela cells were seeded into Minemal EssentialMedium (MEM) supplemented with 5% inactivated foetal calf serum and nonessential amino acids. The seeded cells were incubated overnight at 37°C. in a 5% CO₂ atmosphere. After 24 hours the cells were treated withsolutions of the test compounds in a solvent containing 1 part by volumeof DMSO and 7 parts by volume of MEM supplemented with 10% inactivatedcalf serum, or with the said solvent. Both the solvent and drug treatedcells were incubated for 3 hours at 37° C. and subsequently astandardized inoculum of human rhinovirus was added. During a furtherincubation period at 33° C., the rhinovirus was allowed to grow in theHela cells. Scoring of the results was delayed until a complete (100%)cytopathic effect was obtained in the virus controls (cells treated withsolvent and virus). Anti-viral activity was scored as the lowestconcentration of the tested drug in μg/ml inhibiting at least 75% of thecytopathic effect observed in the virus controls.

Additionally, some of the compounds of the present invention show alsoanalgetic and antitussive properties which properties can bedemonstrated, for example by the Tail Withdrawal Reflex test and theWrithing Test described in Arzneim. Forsch., 25, 1505-1509 (1975) and inArzneim. Forsch., 15, 107-117 (1965).

In view of their useful pharmacological properties, the compounds offormula (I) and their acid-addition salts are very useful in thetreatment of viral diseases.

In order to enhance the ease of administration, the subject compoundsmay be formulated into various pharmaceutical forms. To prepare thepharmaceutical compositions of this invention, an effective amount ofthe particular compound, in base or acid-addition salt form, as theactive ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed.

In the compositions suitable for percutaneous administration, thecarrier optionally comprises a penetration enhancing agent and/or asuitable wettable agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not introduce asignificant deletorious effect on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

Acid addition salts of (I) due to their increased water solubility overthe corresponding base form, are obviously more suitable in thepreparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

In a further aspect of the present invention there is provided a methodof treating viral diseases in warm-blooded animals suffering from saidviral diseases, which method comprises the systemic administration towarm-blooded animals of an anti-virally effective amount of a compoundof formula (I), a pharmaceutically acceptable acid addition salt, apossible stereoisomeric or tautomeric form thereof. Suitable dosesadministered daily to subjects are varying from 0.01 mg to 1 g,preferably from 1 mg to 500 mg.

Preferred methods of treating viral diseases in warm-blooded animalssuffering from said viral diseases, are those methods comprising thesystemic administration to warm-blooded animals of an anti-virallyeffective amount of a compound having the formula ##STR9## apharmaceutically acceptable acid-addition salt and/or a possiblestereoisomeric and/or a tautomeric form thereof, wherein R¹, R² and R³have the previously defined meaning and A¹ is a bivalent radical havingthe formula (a), (b), (c) or (d); provided that

i) when R¹, R² and R³ are hydrogen radicals and A¹ is a radical offormula (b), then R⁴ is other than 3,3-diphenylpropyl;

ii) when R¹ is hydrogen and R² and R³ combined form a bivalentCH═CH--CH═CH radical, then ##STR10## is other than piperidinyl; iii)when R¹ is halo, R² is lower alkyl and R³ is hydrogen, then ##STR11## isother than piperidinyl and hexahydro-1H-azepinyl. iv) when R¹ is chloro,and A¹ is a bivalent radical of formula (b) then R⁴ is other then(dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α-methyl-phenethyl or(2-methylphenyl)methyl.

Preferred compositions within the invention are those comprising aninert carrier and an anti-virally effective amount of a compound offormula (I'), a pharmaceutically acceptable acid-addition salt and/or apossible stereochemically isomeric form and/or a tautomeric formthereof.

An additional feature of the present invention consists in the fact thatsome of the compounds of formula (I) and/or the pharmaceuticallyacceptable acid-addition salts and/or possible stereochemically isomericand/or the possible tautomeric forms thereof are new, which compoundsare represented by the formula ##STR12## wherein R¹, R² and R³ have thepreviously described meaning and A² is a bivalent radical having theformula (a), (c), (d) or ##STR13## wherein m and n have the previouslydescribed meaning and one of the hydrogen atoms within the radical C_(m)H_(2m), C_(m-1) H.sub.(2m-1) or C_(n) H_(2n) may be replaced by loweralkyl or aryl; and R^(4-c) is a member selected from the groupconsisting of aryl; thiazolyl; pyrimidinyl; quinolinyl; loweralkylcarbonyl, lower alkyloxycarbonyl; diaryllower alkyl; phenyl beingsubstituted with arylcarbonyl; pyridinyl, being optionally substitutedwith cyano or lower alkyl; cyclohexyl and cyclohexenyl both beingoptionally substituted with up to two substituents independentlyselected from the group consisting of cyano and aryl; provided that

i) when A² is a radical of formula (c) and R⁶ is hydrogen, then R⁵ isother than hydrogen, hydroxy or lower alkyl;

ii) when R¹, R² and R³ are hydrogen radicals and A² is a radical offormula (b-1), then R^(4-c) is other than 3,3-diphenylpropyl;

iii) when R² and R³ are hydrogen radicals and A² is a radical of formula(a), then R¹ is other than halo;

iv) when R¹ is chloro, R² and R³ are hydrogen radicals and A² is aradical of formula (b-2), then R^(4-c) is other than 2-methoxyphenyl.

v) when R¹ is chloro, and A² is a bivalent radical of formula (b) thenR^(4-c) is other then (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl,α-methyl-phenethyl or (2-methylphenyl)-methyl.

Particularly preferred methods of treating viral diseases inwarm-blooded animals suffering from same, are those methods comprisingthe systemic administration to warm-blooded animals of an anti-virallyeffective amount of a compound having the formula (I") apharmaceutically acceptable acid-addition salt and/or a possiblestereochemically isomeric form and/or a possible tautomeric formthereof.

Particularly preferred compositions within the invention are thosecomprising an inert carrier and an anti-virally effective amount of acompound of formula (I"), a pharmaceutically acceptable acid-additionsalt and/or a possible stereochemically isomeric form and/or a possibletautomeric form thereof.

Within the group of the said new compounds, those compounds of formula(I") are preferred wherein A² is a bivalent radical of formula (b),wherein R^(4-c) is aryl, pyridinyl, pyrimidinyl, lower alkyloxycarbonyl,aryllower alkyl, diaryllower alkyl, quinolinyl, or wherein A² is abivalent radical of formula (c), wherein R⁵ is hydrogen, aryl,arylamino, (aryl) (lower alkyl)amino, hydroxy, indolyl and R⁶ ishydrogen, aryl, arylcarbonyl, (arylcarbonyl)lower alkyl, or wherein A²is a bivalent radical of formula (d).

Particularly preferred new compounds are those wherein the bivalentradical A² is as defined for the preferred new compounds and wherein R²and R³ are both hydrogen radicals.

More particularly preferred new compounds are those wherein R², R³ andA² are as defined for the particularly preferred compounds and whereinin the said bivalent radical A² having the formula (b) m is the integer2 or 3 and n is 2, in the radical A² having the formula (c) m is theinteger 1 or 2 and n is the integer 2, and in the radical A² of formula(d), m is the integer 1 or 2 and n is the integer 2.

Especially preferred new compounds are those wherein R², R³, A², m and nare as defined for the previously mentioned more particularly preferrednew compounds and wherein R¹ is halo, lower alkyloxy, aryloxy, loweralkylthio, arylthio and cyano.

More especially preferred new compounds are those wherein R², R³, A², mand n are as defined for the previously mentioned more particularlypreferred new compounds, and wherein R¹ is halo.

The most preferred compounds within the invention are selected from thegroup consisting of3-bromo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine,3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazineand the pharmaceutically acceptable acid-addition salts thereof.

Some of the compounds of this invention may have several asymmetriccentra in their structure. Pure stereoisomeric forms of the compounds offormula (I) may be obtained by art-known separation procedures. Forexample, diastereomers may be separated by selective crystallization orby application of chromatographic techniques, while enantiomers may beseparated by the selective crystallization of their diastereomeric saltswith optically active acids. Pure stereoisomeric forms may also beobtained by stereospecific syntheses starting from the correspondingstereoisomerically pure forms of the appropriate starting materials.Stereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of this invention.

The following examples are intended to illustrate and not to limit thescope of the present invention in all its aspects. Unless otherwisestated all parts therein are by weight.

EXAMPLES A. Preparation of Intermediates Example 1

A mixture of 221 parts of 4-fluorobenzeneacetonitrile, 700 parts ofsodium methoxide solution 30% and 900 parts of dimethylbenzene wasstirred for 5 minutes. Then there were added dropwise 309 parts ofmethyl 2-propenoate (exothermic reaction: temperature rose to 65° C.).Upon completion, stirring was continuted overnight at refluxtemperature. The methanol was distilled off till an internal temperatureof 110° C. was reached. After cooling, 1000 parts of a hydrochloric acidsolution 6N were added dropwise and the whole was stirred and refluxedfor 5 minutes. Upon cooling, the layers were separated. The organicphase was dried, filtered and evaporated. The residue was stirred andrefluxed for 4 hours together with 500 parts of acetic acid, 500 partsof water and 500 parts of a hydrochloric acid solution. After cooling,the product was extracted with trichloromethane. The extract was washedsuccessively with water, with a diluted sodium hydroxide solution andagain with water till neutralization, dried, filtered and evaporated.The residue was crystallized from 2-propanol, yielding 134.5 parts of1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile; mp. 91.8° C.(intermediate 1).

Example 2

A mixture of 17.6 parts of 1-(phenylmethyl)piperazine, 8.4 parts ofethyl 4-fluorobenzoate and 45 parts of N,N-dimethylacetamide was stirredand refluxed for 22 hours. The reaction mixture was cooled and pouredonto 500 parts of water. The product was extracted three times withbenzene. The combined extracts were washed three times with a lot ofwater, dried, filtered and evaporated. The residue was stirred inhexane. The product was filtered off, washed with hexane and dried invacuo, yielding 12.5 parts (77%) of ethyl4-[4-(phenylmethyl)-1-piperazinyl]benzoate (intermediate 2).

Example 3

A mixture of 14 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate,13 parts of (3-chloro-1-propenyl)benzene, 26.5 parts of sodium carbonateand 240 parts of 4-methyl-2-pentanone was stirred and refluxed overweek-end using a water separator. The reaction mixture was cooled, waterwas added and the layers were separated. The organic phase was dried,filtered and evaporated. The residue was converted into the ethanedioatesalt in 2-propanol and 2-propanone. The salt was filtered off and dried,yielding 23.4 parts of (E)-ethyl4-[methyl(3-phenyl-2-propenyl)amino]-1-piperidinecarboxylateethanedioate (1:1); mp. 160.2° C. (intermediate 3).

Example 4

To a stirred mixture of 19 parts of 1-(phenylmethyl)-4-piperidinol, 15.2parts of N,N-diethylethanamine and 180 parts of methylbenzene were addeddropwise (slowly) 14 parts of benzoyl chloride. Upon completion,stirring was continued for 3 hours at room temperature. The formedhydrochloride salt of benzoyl chloride was filtered off and washed withmethylbenzene. The filtrate was evaporated. The oily residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wasconverted into the hydrochloride salt in 2-propanol. The salt wasfiltered off and dried, yielding 18 parts (54%) of[1-(phenylmethyl)-4-piperidinyl] benzoate hydrochloride; mp. 225.9° C.(intermediate 4).

Example 5

To a stirred mixture of 7.8 parts of sodium amide 5% in benzene and 135parts of methylbenzene was added dropwise a solution of 11.7 parts ofbenzeneacetonitrile in 45 parts of methylbenzene at 25° C. (cooling wasnecessary). After stirring for 30 minutes at 30° C., there was addeddropwise a solution of 24.7 parts of ethyl1-(phenylmethyl)-4-piperidinecarboxylate in 45 parts of methylbenzene at30° C. Upon completion, stirring was continued overnight at 80° C. Thereaction mixture was cooled, 12 parts of ethanol were added and thewhole was poured into ice water. The layers were separated and theaqueous phase was neutralized with acetic acid. The oily product wasextracted with trichloromethane. The extract was dried, filtered andevaporated. The residue was crystallized from 4-methyl-2-pentanone,yielding 12 parts (38%) ofα-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]-benzeneacetonitrile;mp. 191.9° C. (intermediate 5).

To 200 parts of water were added carefully 200 parts of acetic acidwhile stirring and cooling. Then there were added dropwise (slowly) 368parts of sulfuric acid. 90 Parts ofα-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrilewere added and the whole was stirred and refluxed overnight. The aceticacid was evaporated and the residue was poured into crushed ice. Themixture was alkalized with concentrate ammonium hydroxide and the oilyproduct was extracted with trichloromethane. The extract was dried,filtered and evaporated, yielding 79 parts (96.3%) of2-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]ethanone as a residue(intermediate 6).

Example 6

A mixture of 93 parts ofN-(2-chloroethyl)-N-(3-chloropropyl)-4-methylbenzenesulfonamide, 30.3parts of 2,3-dimethylbenzenamine, 63.6 parts of sodium carbonate, 1 partof potassium iodide and 240 parts of cyclohexanol was stirred andrefluxed over weekend using a water separator. After cooling, thereaction mixture was poured into water. The product was extracted withmethylbenzene. The extract was washed twice with water, dried, filteredand evaporated. The residue was crystallized from 2-propanol and a smallamount of tetrahydrofuran. The product was filtered off and dried,yielding 47.8 parts (53.3%) of1-(2,3-dimethylphenyl)hexahydro-4-[(4-methylphenyl)sulfonyl]-1H-1,4-diazepine;mp. 86.2° C. (intermediate 7).

In a similar manner there were also prepared:

1-[2-methoxy-5-(trifluoromethyl)phenyl]piperazine hydrochloride; mp.226.8° C. (intermediate 8);

1-[(4-methylphenyl)sulfonyl]-4-(2,4,6-trimethylphenyl)piperazine(intermediate 9);

1-(3,5-dichlorophenyl)hexahydro-4-[(4-methylphenyl)sulfonyl]-1H-1,4-diazepine(intermediate 10);

1-(3-chlorophenyl)hexahydro-4-[(4-methylphenyl)sulfonyl]-1H-1,4-diazepine;mp. 116.6° C. (intermediate 11);

hexahydro-1-(2-methoxyphenyl)-4[(4-methylphenyl)sulfonyl]-1H-1,4-diazepineas a residue (intermediate 12); and

hexahydro-1[(4-methylphenyl)sulfonyl]-4-[3-(trifluoromethyl)phenyl]-1H-1,4-diazepineas a residue (intermediate 13).

Example 7

to a stirred mixture of 180 parts of1-[(4-methylphenyl)sulfonyl]-4-(2,4,6-trimethylphenyl)piperazine and 450parts of water were added dropwise 675 parts of sulfuric acid. The wholewas stirred and refluxed for 4 hours. After cooling, the whole wastreated with an ammonium hydroxide solution. The product was extractedwith dichloromethane. The extract was dried, filtered and evaporated,yielding 70 parts (69%) of 1-(2,4,6-trimethylphenyl)piperazine as aresidue (intermediate 14).

In a similar manner there were also prepared:

4-(3-methylphenyl)-4-piperidinecarboxamide (intermediate 15);

1-(2,3-dimethylphenyl)hexahydro-1H-1,4-diazepine as a residue(intermediate 16);

hexahydro-1-(2-methoxyphenyl)-1H-1,4-diazepine monohydrochloride; mp.176.6° C. (intermediate 17); and

hexahydro-1-[3-(trifluoromethyl)phenyl]-1H-1,4-diazepinemonohydrochloride; mp. 191.1° C. (intermediate 18).

Example 8

A mixture of 7.9 parts of ethyl 3-oxo-1-pyrrolidinecarboxylate, 5.35parts of 3-methylbenzenamine, 1 part of a solution of thiophene inmethanol 4% and 200 parts of methanol was hydrogenated at normalpressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst10%. After the calculated amount of hydrogen was taken up, the catalystwas filtered off and the filtrate was evaporated, yielding 12.4 parts(100%) of ethyl 3-[(3-methylphenyl)amino]-1-pyrrolidinecarboxylate as aresidue (intermediate 19).

In a similar manner there were also prepared:

N-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinamineethanedioate(1:1); mp. 151.6° C. (intermediate 20);

N-phenyl-1-(phenylmethyl)-3-piperidinamine as a residue (intermediate21);

ethyl 3-[(2,3-dimethylphenyl)amino]-1-pyrrolidinecarboxylate as aresidue (intermediate 22);

ethyl 4-[[3-(trifluoromethyl)phenyl]amino]-1-piperidinecarboxylatemonohydrochloride (intermediate 23);

N-(3-methylphenyl)-1-(phenylmethyl)-3-piperidinamine as a residue(intermediate 24); and

ethyl 3-[[3-(trifluoromethyl)phenyl]amino]-1-pyrrolidinecarboxylate as aresidue (intermediate 25).

Example 9

To a stirred solution of 152 parts of3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzenewere added dropwise 218 parts of ethyl carbonochloridate at roomtemperature. Upon completion, stirring was continued overnight atreflux. After cooling, the reaction mixture was washed with water andhydrochloric acid, dried, filtered and evaporated. The residue wasdistilled, yielding 120.5 parts (83%) of ethyl3-methyl-4-oxo-1-piperidinecarboxylate; bp. 98°-105° C. at 1 mm pressure(intermediate 26).

Example 10

To a stirred and refluxed Grignard complex previously prepared startingfrom a mixture of 4.2 parts of 1-bromo-3-chlorobenzene, 5.4 parts ofmagnesium and 135 parts of tetrahydrofuran were added dropwise 19 partsof 1-(phenylmethyl)-3-piperidinone. Upon completion, stirring wascontinued for 1 hour at reflux temperature. After cooling, the reactionmixture was poured into ice water and 12.5 parts of acetic acid. Thelayers were separated. The aqueous phase was extracted withtrichloromethane. The organic layer was washed with water, dried,filtered and evaporated. The residue was converted into thehydrochloride salt in 2-propanol. the salt was filtered off and dried,yielding 26 parts (76%) of3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride(intermediate 27).

In a similar manner there were also prepared:

ethyl 4-hydroxy-4-(2-thienyl)-1-piperidinecarboxylate; mp. 146.2° C.;(intermediate 28);

ethyl 4-hydroxy-4-(1-naphthalenyl)-1-piperidinecarboxylate; mp.109.2°-114.8° C.; (intermediate 29);

ethyl3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxy-1-pyrrolidinecarboxylateas a residue; (intermediate 30);

ethyl 4-hydroxy-4-(2-naphthalenyl)-1-piperidinecarboxylate as a residue;(intermediate 31);

3-(3-methylphenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride(intermediate 32);

cis-3-methyl-4-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinol as aresidue (intermediate 33);

ethyl cis-4-(3-fluorophenyl)-4-hydroxy-3-methyl-1-piperidinecarboxylateas a residue (intermediate 34);

ethyl cis-4-hydroxy-3-methyl-4-(2-thienyl)-1-piperidinecarboxylate as aresidue (intermediate 35);

ethyl 3-hydroxy-3-(2-theinyl)-1-piperidinecarboxylate (intermediate 36);

3-(3-fluorophenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride(intermediate 37);

ethyl 4-(2,3-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylate(intermediate 38);

3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride(intermediate 39);

3-(3-methylphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride(intermediate 40);

ethyl3-[4-chloro-3-(trifloromethyl)phenyl]-3-hydroxy-1-piperidinecarboxylateas a residue (intermediate 41);

3-(3-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride(intermediate 42);

ethyl 4-hydroxy-4-(3-methoxyphenyl)-3-methyl-1-piperidinecarboxylate asa residue (intermediate 43); and

3-(3-methoxyphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride(intermediate 44).

Example 11

A mixture of 7 parts of3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinol hydrochloride and200 parts of a hydrochloric acid solution 6N was stirred and refluxedovernight. The reaction mixture was evaporated. Water was added and thebase was liberated with ammonium hydroxide. The product was extractedwith trichloromethane. The extract was washed with water, dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (98:2 by volume) as eluent. The first fraction was collectedand the eluent was evaporated, yielding 0.7 parts (12%) of5-(2,3-dimethylphenyl)-1,2,3,4-tetrahydro-1-(phenylmethyl)pyridine as aresidue (intermediate 45). The second fraction was collected and theeluent was evaporated, yielding 5.3 parts (91%) of5-(2,3-dimethylphenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine as aresidue (intermediate 46).

Example 12

A mixture of 8 parts of3-(3-methylphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride and 150parts of a hydrochloric acid solution 6N was stirred and refluxed for 3hours. After cooling, the reaction mixture was evaporated, yielding 7.4parts (100%) of2,3-dihydro-4-(3-methylphenyl)-1-(phenylmethyl)-1H-pyrrole hydrochlorideas a residue (intermediate 47).

In a similar manner there were also prepared:

1,2,3,6-tetrahydro-5-(3-methylphenyl)-1-(phenylmethyl)pyridine as aresidue (intermediate 48); and

5-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridinehydrochloride (intermediate 49).

Example 13

To a stirred solution of 13 parts of3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol in 270 parts ofmethylbenzene were added dropwise 10.9 parts of ethyl carbonochloridateat room temperature. Upon completion, stirring was continued overnightat reflux temperature. After cooling to room temperature, the whole waswashed with water and hydrochloric acid. The organic layer was dried,filtered and evaporated, yielding 7 parts (58%) of ethyl3-(3-chlorophenyl)-3-hydroxy-1-piperidinecarboxylate as a residue(intermediate 50).

Example 14

A mixture of 11.8 parts ofN-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinamine and 120 partsof methanol was hydrogenated at normal pressure and at room temperaturewith 2 parts of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen was taken up, the catalyst was filtered off overHyflo and the filtrate was evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (from 99:1 to 95:5 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was converted into the ethanedioate salt in 2-propanol and2-propanone. The salt was filtered off and dried, yielding 7 parts(79.5%) of N-(2,3-dimethylphenyl)-3-piperidinamine ethanedioate (1:1);mp. 161.6° C. (intermediate 51).

In a similar manner there were also prepared:

ethyl 4-(1-piperazinyl)benzoate; mp. 102.6° C. (intermediate 52);

(4-piperidinyl) benzoate hydrochloride; mp. 236.8° C. (intermediate 53);

N-phenyl-3-piperidinamine; mp. 79.8° C. (intermediate 54);

N-(3-methylphenyl)-3-piperidinamine as a residue (intermediate 55);

4-[(3-methylphenyl)amino]-4-piperidinecarboxamide as a residue(intermediate 56);

2-phenyl-1-(4-piperidinyl)ethanone hydrochloride; mp. 198.6° C.;(intermediate 57);

3-(3-methylphenyl)piperidine as a residue (intermediate 58);

3-(3-methylphenyl)-3-piperidinol hydrochloride (intermediate 59);

cis-3-methyl-4-(3-methylphenyl)-4-piperidinol as a residue (intermediate60);

3-(3-fluorophenyl)-3-piperidinol hydrochloride (intermediate 61);

3-(2,3-dimethylphenyl)-3-piperidinol hydrochloride hemihydrate; mp.135.5° C. (intermediate 62);

3-(2,3-dimethylphenyl)piperidine as a residue (intermediate 63);

3-(3-methylphenyl)-3-pyrrolidinol (intermediate 64);

3-(3-methoxyphenyl)-3-piperidinol hydrochloride as a residue(intermediate 65);

3-(3-fluorophenyl)-3-pyrrolidinol hydrochloride as a residue(intermediate 66); and

3-(3-methoxyphenyl)-3-pyrrolidinol hydrochloride as a residue(intermediate 67).

Example 15

A mixture of 13.10 parts of ethyl3-[(2,3-dimethylphenyl)amino]-1-pyrrolidinecarboxylate, 28 parts ofpotassium hydroxide and 240 parts of 2-propanol was stirred and refluxedfor 6 hours. The reaction mixture was evaporated. The residue was takenup in water. The product was extracted with dichloromethane. The extractwas dried, filtered and evaporated, yielding 6 parts (63%) ofN-(2,3-dimethylphenyl)-3-pyrrolidinamine as a residue (intermediate 68).

In a similar manner there were also prepared:

(E)-N-methyl-N-(3-phenyl-2-propenyl)-4-piperidinamine dihydrochloridehemihydrate; mp. 240.2° C. (intermediate 69);

N-[3-(trifluoromethyl)phenyl]-4-piperidinamine dihydrobromide; mp.253.2° C. (intermediate 70);

N-(3-methylphenyl)-3-pyrrolidinamine ethanedioate(1:2); mp. 180° C.(intermediate 71);

4-(2-thienyl)-4-piperidinol; mp. 145.9° C. (intermediate 72);

4-(1-naphthalenyl)-4-piperidinol; mp. 185.1°-187.8° C. (intermediate73);

3-[4-chloro-3-(trifluoromethyl)phenyl]-3-pyrrolidinol; mp. 138.4°-142.1°C. (intermediate 74);

4-(2-naphthalenyl)-4-piperidinol (intermediate 75);

N-[3-(trifluoromethyl)phenyl]-3-pyrrolidinamine dihydrochloride(intermediate 76);

cis-4-(3-fluorophenyl)-3-methyl-4-piperidinol as a residue (intermediate77);

cis-3-methyl-4-(2-thienyl)-4-piperidinol as a residue (intermediate 78);

3-(2-thienyl)-3-piperidinol (intermediate 79);

3-(3-chlorophenyl)-3-piperidinol hydrochloride (intermediate 80);

4-(2,3-dimethylphenyl)-4-piperidinol (intermediate 81);

4-(3-chlorophenyl)-3-methyl-4-piperidinol as a residue (intermediate82);

3-[4-chloro-3-(trifluoromethyl)phenyl]-3-piperidinol (intermediate 83);and

4-(3-methoxyphenyl)-3-methyl-4-piperidinol as a residue (intermediate84).

Example 16

A mixture of 3 parts of 3-(3-fluorophenyl)-3-piperidinol hydrochlorideand 100 parts of a hydrochloric acid solution 6N was stirred andrefluxed for 3 hours. The reaction mixture was evaporated. The residuewas taken up in water and ammonium hydroxide. The product was extractedwith trichloromethane. The extract was washed with water, dried,filtered and evaporated, yielding 2.2 parts (96%) of5-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine as a residue (intermediate85).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

4-[4-chloro-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridinehydrochloride (intermediate 86):

1,2,3,6-tetrahydro-4-(2-thienyl)pyridine hydrochloride (intermediate87);

1,2,3,6-tetrahydro-4-[3-(trifluoromethyl)phenyl]pyridine as a residue(intermediate 88);

1,2,3,6-tetrahydro-4-(1-naphthalenyl)pyridine hydrochloride; mp. 277.5°C. (intermediate 89);

1,2,3,6-tetrahydro-5-(3-methylphenyl)pyridine hydrochloride(intermediate 90);

3,4-dihydro-3-(2-thienyl)-1H-pyrrole as a residue (intermediate 91); and

3-(2-thienyl)pyrrolidine as a residue (intermediate 92).

Example 17

A mixture of 6.5 parts of5-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridinehydrochloride and 120 parts of methanol was hydrogenated at normalpressure and at 50° C. with 1 part of palladium-on-charcoal catalyst10%. After the calculated amount of hydrogen was taken up, the catalystwas filtered off and the filtrate was evaporated, yielding 4.5 parts(100%) of 3-(3-fluorophenyl)-piperidine hydrochloride as a residue(intermediate 93).

In a similar manner there were also prepared:

4-(2-thienyl)piperidine hydrochloride (intermediate 94); and

3-(3-methylphenyl)pyrrolidine hydrochloride as a residue (intermediate95).

Example 18

A mixture of 21 parts ofN-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine dihydrochloride, 9parts of poly(oxymethylene), 15 parts of potassium acetate, 2 parts of asolution of thiophene in methanol 4% and 200 parts of methanol washydrogenated at normal pressure and at room temperature with 4 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off over Hyflo and thefiltrate was evaporated. From the residue, the free base was liberatedwith ammonium hydroxide and extracted with dichloromethane. The extractwas dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (99:1 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was converted into thehydrochloride salt in 2-propanol. The salt was filtered off and dried,yielding 2.4 parts (75%) ofN-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinaminedihydrochloride hemihydrate; mp. 201.3° C. (intermediate 96).

A mixture of 9 parts ofN-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinaminedihydrochloride hemihydrate and 200 parts of methanol was hydrogenatedat normal pressure and at room temperature with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off over Hyflo and thefiltrate was evaporated. The residue was converted into thehydrochloride salt in 2-propanol. The salt was filtered off and dried,yielding 1.5 parts (60.9%) ofN-methyl-N-(3-methylphenyl)-4-piperidinamine dihydrochloridemonohydrate; mp. 209.1° C. (intermediate 97).

B. Preparation of Final compounds Example 19

A mixture of 47.6 parts of 1H-imidazole, 33.6 parts of sodium hydridedispersion 50% and 750 parts of N,N-dimethylformamide was stirred atroom temperature for 15 minutes. The resulting solution was added to 106parts of 3,6-dichloropyridazine in 750 parts of N,N-dimethylformamideand the whole was further stirred for 2 days at room temperature. Theproduct was extracted with trichloromethane. The extract was dried,filtered and evaporated. The residue was crystalized from methanol. Theproduct was filtered off, washed with petroleumether and dried, yielding48.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine; mp. 182.9° C.(compound 1).

Example 20

A mixture of 3 parts of 3,5-dimethylphenol, 1.25 parts of sodium hydridedispersion 50% and 25 parts of N,N-dimethylformamide was stirred for 15minutes. Then there was added a solution of 4.5 parts of3-chloro-6-(1H-imidazol-1-yl)pyridazine in 25 parts ofN,N-dimethylformamide and the whole was stirred over weekend at 50° C.The reaction mixture was poured onto water and the product was extractedwith trichloromethane. The extract was dried, filtered and evaporated.The residue was crystallized from 2-propanone, yielding 3.5 parts of3-(3,5-dimethylphenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 169.8° C.(compound 2).

In a similar manner there were also prepared:

3-(1H-imidazol-1-yl)-6-(4-methylphenoxyphenoxy)pyridazine; mp. 146.8° C.(compound 3);

3-(1H-imidazol-1-yl)-6-(3-nitrophenoxy)pyridazine; mp. 171.5° C.(compound 4); and

3-(4-chlorophenoxy)-6-(1H-imidazol-1-yl)-pyridazine; mp. 165.8° C.(compound 5).

Example 21

A mixture of 4.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine, 3.2parts of 4-bromophenol, 4.2 parts of sodium carbonate and 80 parts of2-propanone was stirred and refluxed over weekend. The reaction mixturewas evaporated and the residue was taken up in water and2,2'-oxybispropane. The layers were separated. The organic phase wasdried, filtered and evaporated. The residue was crystallized from2-propanol, yielding 3.5 parts of3-(4-bromophenoxy)-6-(1H-imidazol-1-yl)pyridazine; mp. 168.4° C.(compound 6).

Example 22

A mixture of 4.35 parts of1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, 3.3 parts of1-(3-piperazinyl)pyridazine, 0.2 parts of 4-methylbenzenesulfonic acidand 360 parts of methylbenzene was stirred and refluxed overnight usinga water separator. The reaction mixture was cooled and evaporated,yielding 7.3 parts (100%) of1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl[-3-cyclohexenecarbonitrileas a residue (compound 7).

To a stirred mixture of 7.3 parts of1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexenecarbonitrile,1 part of sodium methoxide solution 30% and 240 parts of methanol wereadded portionwise 0.8 parts of sodium borohydride. Upon completion,stirring was continued overnight at room temperature. The reactionmixture was poured onto ice water and the product was extracted withtrichloromethane. The extract was dried, filtered and evaporated. Theresidue was crystallized from 2-propanol, yielding 4.5 parts (61.5%) of1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]cyclohexanecarbonitrile;mp. 188.7° C. (compound 8).

Example 23

A mixture of 3.1 parts of 3,6-dichloropyridazine, 3 parts of1-(2-fluorophenyl)piperazine, 3.2 parts of sodium carbonate, 0.1 partsof potassium iodide and 72 parts of N,N-dimethylformamide was stirredand heated over weekend at 60° C. The reaction mixture was poured intowater. The precipitated product was filtered off and dissolved intrichloromethane. The organic layer was dried, filtered and evaporated.The residue was purified by filtration over silica gel using a mixtureof trichloromethane and methanol (98:2 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of 2-propanol and 2,2'-oxybispropane,yielding 4.5 parts (77%) of3-chloro-6-[4-(2-fluorophenyl)-1-piperazinyl]pyridazine; mp. 148.0° C.(compound 9).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

    __________________________________________________________________________     ##STR14##                                                                                                      mp. in                                      No. R.sup.1 R.sup.2                                                                           A                 °C.                                  __________________________________________________________________________    10  Cl      H                                                                                  ##STR15##        107.9                                       11                                                                                 ##STR16##                                                                            H                                                                                  ##STR17##        177.7                                       12  Cl      H                                                                                  ##STR18##        119.8                                       13  Cl      H                                                                                  ##STR19##        226.2                                       14  Cl      CH.sub.3                                                                           ##STR20##        152.7                                       15  Cl      H                                                                                  ##STR21##        149.8                                       16  Cl      CH.sub.3                                                                           ##STR22##        163.5                                       17  Cl      H                                                                                  ##STR23##        191.4                                       18  Cl      H                                                                                  ##STR24##        156.8                                       19  Cl      H                                                                                  ##STR25##        160.6                                       20  Cl      CH.sub.3                                                                           ##STR26##        176.6                                       21  Cl      H                                                                                  ##STR27##        122.7                                       22  Cl      H                                                                                  ##STR28##        107.5                                       23  Cl      H                                                                                  ##STR29##         69.8                                       __________________________________________________________________________

Example 24

A mixture of 2.7 parts of 3,6-difluoropyridazine, 4.6 parts of1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonateand 90 parts of N,N-dimethylformamide was stirred overnight at 60° C.The reaction mixture was poured into water. The product was filteredoff, washed with water and crystallized from 2-propanol, yielding 3parts (46%) of3-fluoro-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp.131.5° C. (compound 24).

In a similar manner there were also prepared:

3-[4-(2,3-dimethylphenyl)-1-piperazinyl]-6-fluoropyridazine; mp. 144.1°C. (compound 25);

3-fluoro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 128.1° C.(compound 26) and

3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-fluoropyridazine;mp. 105.2° C. (compound 27).

Example 25

A mixture of 4.5 parts of 3,6-dichloropyridazine, 5.2 parts of1,2,3,6-tetrahydro-4-(3-methylphenyl)pyridine, 5.3 parts of sodiumcarbonate and 72 parts of N,N-dimethylformamide was stirred and heatedovernight at about 70° C. The reaction mixture was evaporated and waterwas added to the residue. The product was extracted withtrichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by filtration over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from 2-propanol. The product was filtered off and dried,yielding 2.1 parts (24%) of3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine;mp. 122.2° C. (compound 28).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

    __________________________________________________________________________     ##STR30##                                                                                                         Salt or                                                                              mp. in                            R.sup.1       A                      base   °C.                        __________________________________________________________________________    29    Cl                                                                                     ##STR31##             base   183.3                             30    Cl                                                                                     ##STR32##             base   133.5                             31    Cl                                                                                     ##STR33##             base   221.9                             32    Cl                                                                                     ##STR34##             base   146.6                             33    Cl                                                                                     ##STR35##             base   172.0                             34    Cl                                                                                     ##STR36##             base   144.5                             35    Cl                                                                                     ##STR37##             base   188.6                             36    Cl                                                                                     ##STR38##             base   162.6                             37    Cl                                                                                     ##STR39##             base   207.7                             38    Cl                                                                                     ##STR40##             base   164.6                             39    Cl                                                                                     ##STR41##             base   140.1                             40    Cl                                                                                     ##STR42##             base   118.2                             41    Cl                                                                                     ##STR43##             base   200.6                             42    Cl                                                                                     ##STR44##             base   155.8                             43    Cl                                                                                     ##STR45##             base   124.4                             44    Cl                                                                                     ##STR46##             base   160.0                             45    Cl                                                                                     ##STR47##             base   156.4                             46    Cl                                                                                     ##STR48##             base   114.8                             47    Cl                                                                                     ##STR49##             base   153.1                             48    Cl                                                                                     ##STR50##             base   177.3                             49    Cl                                                                                     ##STR51##             base   262.5                             50    Cl                                                                                     ##STR52##             base   161.3                             51    Cl                                                                                     ##STR53##             base   149.5                             52    Cl                                                                                     ##STR54##             base   145.9                             53    Cl                                                                                     ##STR55##             base   203.5                             54    Cl                                                                                     ##STR56##             base   149.6                             55    Cl                                                                                     ##STR57##             base   167.2                             56    Cl                                                                                     ##STR58##             base   164.7                             57    Cl                                                                                     ##STR59##             HCl    218.0                             58    Cl                                                                                     ##STR60##             base   161.9                             59    Cl                                                                                     ##STR61##             HCl    142.2                             60    Cl                                                                                     ##STR62##             base   123.0                             61    Cl                                                                                     ##STR63##             HCl    176.5                             62    Cl                                                                                     ##STR64##             base   185.2                             63    Cl                                                                                     ##STR65##             base   118.8                             64    Cl                                                                                     ##STR66##             base   174.9                             65    Cl                                                                                     ##STR67##             base   224.4                             66    Cl                                                                                     ##STR68##             base   136.5                             67    Cl                                                                                     ##STR69##             base   172.9                             68    Cl                                                                                     ##STR70##             base   147.6                             69    Cl                                                                                     ##STR71##             HCl    194.5                             70    Cl                                                                                     ##STR72##             base   221.8                             71    Cl                                                                                     ##STR73##             base   95.2                              72    Cl                                                                                     ##STR74##             base   199.6                             73    Cl                                                                                     ##STR75##             base   167.9                             74    Cl                                                                                     ##STR76##             base   120.9                             75    Cl                                                                                     ##STR77##             base   80.4                              76    Cl                                                                                     ##STR78##             base   119.0                             77    Cl                                                                                     ##STR79##             base   120.8                             78    Cl                                                                                     ##STR80##             base   178.7                             79    Cl                                                                                     ##STR81##             base   140.4                             80    Cl                                                                                     ##STR82##             base   163.2                             81    Cl                                                                                     ##STR83##             base   148.0                             82    Cl                                                                                     ##STR84##             base   237.8                             83    Cl                                                                                     ##STR85##             base   126.0                             84    Cl                                                                                     ##STR86##             HCl    173.8                             85    Cl                                                                                     ##STR87##             base   127.9                             86    Cl                                                                                     ##STR88##             base   163.8                             87    Cl                                                                                     ##STR89##             base   162.7                             88    Cl                                                                                     ##STR90##             base   152.0                             89    Cl                                                                                     ##STR91##             base   207.7                             90    Cl                                                                                     ##STR92##             base   156.4                             91    Cl                                                                                     ##STR93##             base   118.9                             92    Cl                                                                                     ##STR94##             base   206.0                             93    Cl                                                                                     ##STR95##             base   147.0                             94    Cl                                                                                     ##STR96##             base   137.5                             95    Cl                                                                                     ##STR97##             base   134.7                             96    Cl                                                                                     ##STR98##             base   134.7                              97*  Cl                                                                                     ##STR99##             base   154.0                             98    Cl                                                                                     ##STR100##            base   153.3                              99*  Cl                                                                                     ##STR101##            base   160.5                             100*  Cl                                                                                     ##STR102##            base   148.1                             101   Cl                                                                                     ##STR103##            base   182.7                             102   Cl                                                                                     ##STR104##            base   156.8                             103   Cl                                                                                     ##STR105##            base   175.0                             104   Cl                                                                                     ##STR106##            base   201.8                             105   Cl                                                                                     ##STR107##            HCl    200                               106   Cl                                                                                     ##STR108##            base   208.4                             107   Cl                                                                                     ##STR109##            base   169.4                             108   Cl                                                                                     ##STR110##            base   105.1                             109   Cl                                                                                     ##STR111##            base   161.5                             110   Cl                                                                                     ##STR112##            base   123.1                             111   Cl                                                                                     ##STR113##            base   156.6                             112   Cl                                                                                     ##STR114##            base   138.4                             113                                                                                  ##STR115##                                                                            ##STR116##            base   185.5                             114   Cl                                                                                     ##STR117##            base   136.5                             115   Cl                                                                                     ##STR118##            base   106.2                             116   Cl                                                                                     ##STR119##            base   147.3                             117   Cl                                                                                     ##STR120##            base   196.1                             118   Cl                                                                                     ##STR121##            HCl.1/2H.sub.2 O                                                                     266.7                             119   Cl                                                                                     ##STR122##            base   173.7                             120   NC                                                                                     ##STR123##            base   179.8                             121   Cl                                                                                     ##STR124##            base   204.5                             122   Cl                                                                                     ##STR125##            HCl    196.1                             123   Cl                                                                                     ##STR126##            base   125.1                             124   CH.sub.3 OOC                                                                           ##STR127##            base   159.6                             125                                                                                  ##STR128##                                                                            ##STR129##            base   164.8                             126   Cl                                                                                     ##STR130##            base   156.6                             127   CH.sub.3 OOC                                                                           ##STR131##            base   --                                128   Cl                                                                                     ##STR132##            base   210.7                             129   I                                                                                      ##STR133##            base   145.5                             130   CN                                                                                     ##STR134##            base   138.0                             131   Cl                                                                                     ##STR135##            base   --                                132   Cl                                                                                     ##STR136##            base   --                                133   Cl                                                                                     ##STR137##            base   --                                134   Cl                                                                                     ##STR138##            base   --                                __________________________________________________________________________     *cis form                                                                

In a similar manner there was also prepared:

ethyl 4-(6-chloro-5-methyl-3-pyridazinyl)-1-piperazinecarboxylate; mp.132.2° C. (compound 135).

Example 26

A mixture of 5 parts of 1-(3-methylphenyl)piperazine dihydrochloride,10.6 parts of sodium carbonate and 180 parts of N,N-dimethylformamidewas stirred for 1 hour at 65° C. Then there were added 7.2 parts of3,6-dibromopyridazine and the whole was stirred overnight at about 65°C. The reaction mixture was poured into ice water. The product wasfiltered off and dissolved in dichloromethane. The solution was washedtwice with water, dried, filtered and evaporated. The residue wascrystallized from ethanol. The product was filtered off and dried,yielding 4.1 parts (61.5%) of3-bromo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 145.7° C.(compound 136).

In a similar manner there were also prepared:

3-bromo-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]pyridazine; mp. 166.7°C. (compound 137);

3-bromo-6-[4-(3-chlorophenyl)-1-piperazinyl]pyridazine; mp. 158.7° C.(compound 138);

3-bromo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp.154.3° C. (compound 139);

3-bromo-6-[4-(2-methoxyphenyl)-1-piperazinyl]pyridazine; mp. 164.8° C.(compound 140);

3-bromo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperidinyl]pyridazinemonohydrochloride; mp. 222.5° C. (compound 141);

3-bromo-6-[3,6-dihydro-4-[3-(trifluoromethyl)phenyl]-1(2H)-pyridinyl]-pyridazine;mp. 130.6° C. (compound 142);

1-(6-bromo-3-pyridazinyl)-4-(3-chlorophenyl)-hexahydro-1H-1,4-diazepine;mp. 148.8° C. (compound 143);

3-bromo-6-[4-(3-bromophenyl)-1-piperazinyl]pyridazine; mp. 179.8° C.(compound 144); and

3-bromo-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-pyridazine;mp. 127.1° C. (compound 145);

Example 27

A mixture of 4.5 parts of 3,6-dichloropyridazine, 4.9 parts ofN-[3-(trifluoromethyl)phenyl]-3-piperidinamine, 6.4 parts of sodiumcarbonate and 180 parts of N,N-dimethylformamide was stirred overnightat about 65° C. The reaction mixture was poured into ice water and theproduct was extracted with dichloromethane. The extract was dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (99:1 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized from2-propanol. The product was filtered off (the filtrate was set aside)and dried, yielding 1.2 parts (16.8%) of1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine;mp. 92.6° C. (compound 146). The filtrate, which was set aside, wasconverted into the hydrochloride salt in 2-propanol. The salt wasfiltered off and dried, yielding 2.6 parts (32.9%) of1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl[-3-piperidinaminemonohydrochloride; mp. 173.5° C. (compound 147).

Example 28

A mixture of 3 parts of 3,6-dichloropyridazine, 6.1 parts ofN-[3-(trifluoromethyl)phenyl]-4-piperidinamine dihydrobromide, 6.4 partsof sodium carbonate and 180 parts of N,N-dimethylacetamide was stirredfor 24 hours at 60° C. After cooling to room temperature, the reactionmixture was poured onto water. The product was extracted withmethylbenzene. The extract was washed with water, dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol (97:3 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from 2,2'-oxybispropane. Theproduct was filtered off and dried, yielding 2.5 parts (47%) of1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-4-piperidinamine;mp. 117.9° C. (compound 148).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

    __________________________________________________________________________     ##STR139##                                                                                                         Salt or    mp. in                       No.                                                                              R.sup.1                                                                         R.sup.2                                                                             R.sup.3                                                                              A                   base       °C.                   __________________________________________________________________________    149                                                                              Cl                                                                              H     H                                                                                     ##STR140##         base       209.7                        150                                                                              Cl                                                                              H     H                                                                                     ##STR141##         base       184.7                        151                                                                              Cl                                                                              H     H                                                                                     ##STR142##         base       127.0                        152                                                                              Cl                                                                              H     H                                                                                     ##STR143##         base       197.4                        153                                                                              Cl                                                                              H     H                                                                                     ##STR144##         base       160.5                        154                                                                              Cl                                                                              H     H                                                                                     ##STR145##         base       124.4                        155                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR146##         base       209.2                        156                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR147##         base       178.6                        157                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR148##         base       170.2                        158                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR149##         base       167.2                        159                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR150##         base       167.0                        160                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR151##         base       135.6                        161                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR152##         base       225.6                        162                                                                              Cl                                                                              H     H                                                                                     ##STR153##         base       196.3                        163                                                                              Cl                                                                              H     H                                                                                     ##STR154##         base       155.5                        164                                                                              Cl                                                                              H     H                                                                                     ##STR155##         base       195.1                        165                                                                              Cl                                                                              H     H                                                                                     ##STR156##         base       157.1                        166                                                                              Cl                                                                              H     H                                                                                     ##STR157##         base       137.1                        167                                                                              Cl                                                                              H     H                                                                                     ##STR158##         base       136.8                        168                                                                              Cl                                                                              H     H                                                                                     ##STR159##         1/2(COOH).sub.2                                                                          155.2                        169                                                                              Cl                                                                              CHCHCHCH                                                                                    ##STR160##         base       218.5                        170                                                                              Cl                                                                              H     H                                                                                     ##STR161##         base       132.7                        171                                                                              Cl                                                                              H     H                                                                                     ##STR162##         base       130.2                        172                                                                              Cl                                                                              H     H                                                                                     ##STR163##         base       121.7                        173                                                                              Cl                                                                              H     H                                                                                     ##STR164##         base       156.2                        174                                                                              Cl                                                                              H     H                                                                                     ##STR165##         base       170.4                        175                                                                              Cl                                                                              H     H                                                                                     ##STR166##         base       144.7                        176                                                                              Cl                                                                              H     H                                                                                     ##STR167##         base       138.0                        177                                                                              Cl                                                                              H     H                                                                                     ##STR168##         base         95.0                       178                                                                              Cl                                                                              H     H                                                                                     ##STR169##         base       107.5                        179                                                                              Cl                                                                              H     H                                                                                     ##STR170##         HBr 1/2CH.sub.3CHOHCH.sub.3                                                              193.0                        180                                                                              Cl                                                                              H     H                                                                                     ##STR171##         base       104.4                        181                                                                              Cl                                                                              H     H                                                                                     ##STR172##         base       154.0                        182                                                                              Cl                                                                              H     H                                                                                     ##STR173##         base       121.7                        183                                                                              Cl                                                                              H     H                                                                                     ##STR174##         base        91.5                        184                                                                              Cl                                                                              H     H                                                                                     ##STR175##         base       119.3                        185                                                                              Br                                                                              H     H                                                                                     ##STR176##                                                                                        ##STR177##                                                                              197.3                        186                                                                              Cl                                                                              H     H                                                                                     ##STR178##         base       183.7                        187                                                                              Cl                                                                              H     H                                                                                     ##STR179##         base       115.7                        188                                                                              Cl                                                                              H     H                                                                                     ##STR180##         base       164.4                        189                                                                              Cl                                                                              H     H                                                                                     ##STR181##         base        94.6                        190                                                                              Cl                                                                              H     H                                                                                     ##STR182##         base       127.0                        191                                                                              Cl                                                                              H     H                                                                                     ##STR183##         HCl        193.8                        192                                                                              Cl                                                                              H     H                                                                                     ##STR184##         base       102.1                        193                                                                              Cl                                                                              H     H                                                                                     ##STR185##         base       129.8                        194                                                                              Cl                                                                              H     H                                                                                     ##STR186##         base       121.5                        195                                                                              Cl                                                                              H     H                                                                                     ##STR187##         base       138.4                        196                                                                              Cl                                                                              H     H                                                                                     ##STR188##         base        74.7                        197                                                                              Cl                                                                              H     H                                                                                     ##STR189##         base       168.0                        198                                                                              Cl                                                                              H     H                                                                                     ##STR190##         base       115.1                        199                                                                              Cl                                                                              H     H                                                                                     ##STR191##         base       179.5                        200                                                                              Cl                                                                              H     H                                                                                     ##STR192##         base       157.9                        201                                                                              Cl                                                                              H     H                                                                                     ##STR193##         base       119.3                        __________________________________________________________________________

Example 29

A mixture of 5.2 parts of 3,6-diiodopyridazine, 3.5 parts of1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonateand 90 parts of N,N-dimethylacetamide was stirred and heated overnightat 70° C. The reaction mixture was poured onto water. The precipitatedproduct was filtered off and crystallized from 2-propanol, yielding 3.2parts (48%) of3-iodo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp.144.6° C. (compound 202).

In a similar manner there were also prepared:

3-iodo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 163.1° C.(compound 203);

3-[4-(3-chlorophenyl)-1-piperazinyl]-6-iodopyridazine; mp. 165.0° C.(compound 204);

3-[4-(2,3-dimethylphenyl)-1-piperazinyl]-6-iodopyridazine; mp. 179.4° C.(compound 205); and

3-iodo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperidinyl]pyridazine; mp.106.8° C. (compound 206).

Example 30

A mixture of 4.6 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 6.4parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone wasdistilled azeotropically to dry. 3.3 Parts of 3,6-dichloropyridazinewere added and the whole was stirred and refluxed for 48 hours using awater separator. After cooling, water was added and the product wasextracted with dichloromethane. The organic layer was dried, filteredand evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol (99:1 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from 2-propanol, yielding 2.6parts (37.9%) of3-chloro-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp.149.4° C. (compound 207).

Example 31

To a stirred solution of 7.5 parts of 3,6-dichloropyridazine in 75 partsof N,N-dimethylformamide was added dropwise a solution of 8 parts ofethyl 1-piperazinecarboxylate and 5.6 parts of N,N-diethylethanamine in25 parts of N,N-dimethylformamide. Upon completion, the whole wasstirred overnight at a temperature of about 50° C. After cooling, thereaction mixture was poured onto water and the product was extractedwith trichloromethane. The organic layer was dried, filtered andevaporated. The residue was crystallized from 2-propanol, yielding 3.6parts of ethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate; mp.123.8° C. (compound 208).

Example 32

A mixture of 3.2 parts of 3-chloro-6-(methylsulfonyl)pyridazine, 3 partsof 1-(3-methylphenyl)piperazine, 2 parts of N,N-diethylethanamine and180 parts of benzene was stirred for 24 hours at reflux. The reactionmixture was evaporated. Water was added to the residue. The precipitatedproduct was filtered off, washed with water and dissolved intrichloromethane. The solution was dried, filtered and evaporated. Theresidue was crystallized from methanol. The product was filtered off anddried, yielding 5 parts (89%) of3-[4-(3-methylphenyl)-1-piperazinyl]-6-(methylsulfonyl)pyridazine; mp.201° C. (compound 209).

In a similar manner there were also prepared:

3-[3-(3-methylphenyl)-1-piperazinyl]-6-(methylsulfonyl)pyridazine; mp.146.9° C. (compound 210);

3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-(methylsulfonyl)pyridazine;mp. 179.8° C. (compound 211); and

3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-(methylsulfinyl)pyridazine;mp. 131.0° C. (compound 212).

Example 33

A mixture of 3.3 parts of 3,6-dichloropyridazine, 3.3 parts of1-(2-pyridinyl)piperazine, 1.5 parts of sodium hydrogencarbonate and 120parts of ethanol was stirred and refluxed over weekend. The reactionmixture was evaporated. Water was added to the residue and the productwas extracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol (99:1 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from a mixture of 2-propanoland tetrahydrofuran, yielding 2.5 parts (45.3%) of3-chloro-6-[4-(2-pyridinyl)-1-piperazinyl]pyridazine; mp. 194.7° C.(compound 213).

Example 34

A mixture of 3.2 parts of 3-chloro-6-(methylthio)pyridazine, 3.14 partsof 1,2,3,6-tetrahydro-4-(3-methylphenyl)pyridine hydrochloride, 5.3parts of sodium carbonate and 80 parts of 1-butanol was stirred for 48hours at reflux temperature. The reaction mixture was evaporated. Waterwas added. The product was extracted with trichloromethane. The extractwas dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (98:2 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized from2-propanol. The product was filtered off and dried, yielding 0.8 parts(18%) of3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-(methylthio)pyridazine;mp. 129.8° C. (compound 214).

Example 35

To a stirred solution of 300 parts of hexahydro-1H-1,4-diazepine in 900parts of methylbenzene were added 75 parts of 3,6-dichloropyridazine.The whole was stirred and refluxed for 4 hours. The reaction mixture wasevaporated. Water was added to the residue. The product was extractedwith trichloromethane. The extract was dried, filtered and evaporated.The residue was converted into the hydrochloride salt in 2-propanol andethanol. The salt was filtered off and dried, yielding 28 parts (22%) of1-(6-chloro-3-pyridazinyl)hexahydro-1H-1,4-diazepine monohydrochloride(compound 215).

In a similar manner there was also prepared:

1-(6-chloro-5-methyl-3-pyridazinyl)hexahydro-1H-1,4-diazepine as aresidue (compound 216).

Example 36

A mixture of 3.9 parts of 3,6-dichloro-4,5-dimethylpyridazine, 4.2 partsof 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassiumcarbonate was stirred and heated for 4 hours in an oil bath at 190° C.After cooling, the mixture was taken up in water and trichloromethane.The organic layer was separated, dried, filtered and evaporated. Theresidue was crystallized from 2-propanol. The product was filtered offand dried, yielding 2 parts (30%) of3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine;mp. 194.5° C. (compound 217).

In a similar manner there were also prepared:

3-chloro-4,5-dimethyl-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine;mp. 172.9° C. (compound 218); and

4-(3-methylphenyl)-1-(6-methyl-3-pyridazinyl)-4-piperidinol; mp. 131.5°C. (compound 219).

Example 38

A mixture of 3.5 parts of N-(6-chloro-3-pyridazinyl)acetamide, 3.6 partsof 1-(3-methylphenyl)piperazine and 2.8 parts of potassium carbonate wasstirred for 7 hours in an oil bath at 160° C. After cooling,trichloromethane and water were added. The layers were separated. Theorganic layer was dried, filtered and evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol (97:3 by volume) as eluent. The secondfraction was collected and the eluent was evaporated. The residue wasconverted into the hydrochloride salt in 2-propanol and 2-propanone. Thesalt was filtered off and dried, yielding 0.5 parts (6.6%) of6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinamine dihydrochloride;mp. 178.5° C. (compound 220).

Example 38

A mixture of 4 parts of 6-chloro-3-(4-ethylphenoxy)pyridazine and 6parts of 1-(3-methylphenyl)piperazine was stirred and heated for 3 hoursin an oil bath at 110° C. The whole was allowed to stand overnight.Concentrate ammonium hydroxide and trichloromethane were added. Theprecipitate was filtered off and the filtrate was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (95:5 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized from2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7parts (27%) of3-(4-ethylphenoxy)-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp.106.6° C. (compound 221).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

3-methyl-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 152.9° C.(compound 222); and

3-[4-(3-methylphenyl)-1-piperazinyl]-6-(methylthio)pyridazine; mp.145.0° C. (compound 223).

Example 39

A mixture of 22 parts of ethyl4-(6-chloro-5-methyl-3-pyridazinyl)-1-piperazinecarboxylate, 28 parts ofpotassium hydroxide and 160 parts of 1-butanol was stirred overnight atreflux temperature. The reaction mixture was evaporated. Water wasadded. The product was extracted with trichloromethane. The extract wasdried, filtered and evaporated. 2,2'-Oxybispropane was added. Theproduct was filtered off and dried, yielding 17 parts (100%) of3-chloro-4-methyl-6-(1-piperazinyl)pyridazine (compound 224).

Example 40

A mixture of 6 parts of ethyl[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]carbamate and 60 parts ofconcentrate hydrochloric acid was stirred and refluxed for 24 hours. Thereaction mixture was evaporated. Water was added and the whole wastreated with concentrate ammonium hydroxide. The product was extractedwith trichloromethane. The extract was dried, filtered and evaporated,yielding 3.8 parts (82%) of 1-(6-chloro-3-pyridazinyl)-4-piperidinamine;mp. 260° C. (dec.) (compound 225).

Example 41

A mixture of 3.6 parts of 3-chloro-6-(1-piperazinyl)pyridazinemonohydrochloride, 5.3 parts of sodium carbonate and 90 parts ofN,N-dimethylacetamide was stirred for a while at 60° C. Then there wereadded 3 parts of (3-bromopropyl)benzene and the whole was stirredovernight at 60° C. The reaction mixture was poured into water. Theproduct was filtered off and converted into the hydrochloride salt in2-propanol. The salt was filtered off and dried, yielding 3.2 parts(60%) of 3-chloro-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazinemonohydrochloride; mp. 207.3° C. (compound 226) In a similar mannerthere were also prepared:

3-chloro-4-methyl-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazinemonohydrochloride 1-butanol(1:1).monohydrate; mp. 187.2° C. (compound227);

3-methoxy-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazine; mp. 78.4° C.(compound 228);

3-[4-(3-phenylpropyl)-1-piperazinyl]pyridazine dihydrochloride.monohydrate; mp. 209.0° C. (compound 229); and

1-acetyl-4-(6-chloro-3-pyridazinyl)piperazine; mp. 153.6° C. (compound230).

Example 42

A mixture of 3 parts of 3-chloro-6-(1-piperazinyl)pyridazine, 2 parts ofbenzeneacetylaldehyde, 1 part of a solution of thiophene in methanol 4%and 200 parts of methanol was hydrogenated at normal pressure and atroom temperature with 2 parts of platinum-on-charcoal catalyst 5%. Afterthe calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated. The residue wascrystallized from 2-propanol. The product was filtered off and dried,yielding 1.5 parts (33%) of3-chloro-6-[4-(2-phenylethyl)-1-piperazinyl]pyridazine; mp. 140.0° C.(compound 231).

In a similar manner there were also prepared:

3-(4-butyl-1-piperazinyl)-6-chloropyridazine (E)-2-butenedioate(1:1);mp. 188.2° C. (compound 232);

3-chloro-6-(4-cyclohexyl-1-piperazinyl)pyridazine; mp. 187.2° C.(compound 233); and

1-(6-chloro-3-pyridazinyl)-N-(phenylmethyl)-4-piperidinamine; mp. 93.8°C. (compound 234).

Example 43

A mixture of 4 parts of1-(6-chloro-3-pyridazinyl)-4-(3-methoxyphenyl)-4-piperidinol, 80 partsof ethanol and 50 parts of a hydrochloric acid solution 6N was stirredfor 6 hours at reflux temperature. The reaction mixture was evaporated.Water was added and the whole was treated with concentrate ammoniumhydroxide. The product was extracted with trichloromethane. The extractwas dried, filtered and evaporated. The residue was crystallized from2-propanol. The product was filtered off and dried, yielding 2.5 parts(64%) of3-chloro-6-[3,6-dihydro-4-(3-methoxyphenyl)-1(2H)-pyridinyl]pyridazine;mp. 126.4° C. (compound 235).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

3-chloro-6-[4-(3-chlorophenyl)-3,6-dihydro-1(2H)-pyridinyl]pyridazine;mp. 133.9° C. (compound 236);

3-chloro-6-(3,4-dihydro-5-phenyl-1(2H)-pyridinyl)pyridazine; mp. 146.0°C. (compound 237);

3-chloro-6-[3,4-dihydro-5-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine;mp. 160.0° C. (compound 238);

3-chloro-6-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]pyridazine;mp. 124.7° C. (compound 239);

3-chloro-6-[4-(2,3-dimethylphenyl)-3,6-dihydro-1(2H)-pyridinyl]pyridazine;mp. 144.2° C. (compound 240);

3-chloro-6-[4-(3-chlorophenyl)-3,6-dihydro-5-methyl-1(2H)-pyridinyl]pyridazine;mp. 88.5° C. (compound 241);

3-chloro-6-[3,4-dihydro-5-[3-(trifluoromethyl)phenyl]-1(2H)-pyridinyl]pyridazine;mp. 163.2° C. (compound 242);

3-chloro-6-[3,6-dihydro-5-[3-(trifluoromethyl)phenyl]-1(2H)-pyridinyl]pyridazine;mp. 112.5° C. (compound 243);

3-chloro-6-[5-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]pyridazine;mp. 134.9° C. (compound 244);

3-chloro-6-[3,4-dihydro-5-(3-methoxyphenyl)-1(2H)-pyridinyl]pyridazine;mp. 129.1° C. (compound 245);

3-chloro-6-[5-(2,3-dimethylphenyl)-3,4-dihydro-1(2H)-pyridinyl]pyridazine;mp. 148.8° C. (compound 246);

3-chloro-6-[3,6-dihydro-4-(2-naphthalenyl)-1(2H)-pyridinyl]pyridazinemonohydrochloride hemihydrate; mp. 187.2° C. (compound 247);

3-chloro-6-[3-(3-methylphenyl)-2H-pyrrol-1(5H)-yl]pyridazine; mp. 198.1°C. (compound 248);

3-chloro-6-[2,3-dihydro-4-(3-methylphenyl)-1H-pyrrol-1-yl]pyridazine;mp. 195.3° C. (compound 249);

3-chloro-6-[3,6-dihydro-4-(2-phenylethyl)-1(2H)-pyridinyl]pyridazine;mp. 104.2° C. (compound 250);

3-chloro-6-[5-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)pyridinyl]pyridazine;mp. 140.9° C. (compound 251);

3-chloro-6-[3-(3-fluorophenyl)-2,3-dihydro-1H-pyrrol-1-yl]pyridazine;mp. 213.0° C. (compound 252);

3-chloro-6-[3-(3-fluorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]pyridazine;mp. 228.8° C. (compound 253);

3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-methylpyridazine;mp. 123.4° C. (compound 254);

3-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-methoxypyridazine;mp. 116.4° C. (compound 255); and

3-butoxy-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine;mp. 97.8° C. (compound 256).

Example 44

To a stirred mixture of 80 parts of 1-butanol, 0.4 parts of sodiumhydroxide and 0.94 parts of phenol were added 2.2 parts of3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine at 60° C. Thewhole was stirred and refluxed over weekend. The reaction mixture wasevaporated. The residue was crystallized from 2,2'-oxybispropane. Theproduct was filtered off and dried, yielding 2 parts (64%) of3-butoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 105.2° C.(compound 257).

Example 45

To a stirred sodium methoxide solution, previously prepared startingfrom 1.6 parts of sodium in 24 parts of methanol, were added 4 parts of3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole wasstirred and refluxed for 40 hours. After cooling, 25 parts of water wereadded. The product was filtered off, washed with water and dissolved intrichloromethane. The organic layer was dried, filtered and evaporated.The residue was crystallized from a mixture of 2-propanol and2,2'-oxybispropane. The product was filtered off and dried, yielding 2parts (50%) of 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine;mp. 137.1° C. (compound 258).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

3-[4-(3-fluorophenyl)-3,4-dihydro-1(2H)-pyridinyl]-6-methoxypyridazine;mp. 85.2° C. (compound 259);

3-[3,6-dihydro-4-(2,3-dimethylphenyl)-1(2H)-pyridinyl]-6-methoxypyridazine;mp. 110.8° C. (compound 260);

1-(6-methoxy-3-pyridazinyl)-4-(3-methylphenyl)-4-piperidinol; mp. 125.6°C. (compound 261);

3-[3,4-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-ethoxypyridazine;mp. 84.3° C. (compound 262); and

1-(6-butoxy-3-pyridazinyl)-4-(3-methylphenyl)-4-piperidinol; mp. 106.7°C. (compound 263).

Example 46

A mixture of 1.9 parts of phenol, 2.9 parts of3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 2.76 partsof potassium carbonate was stirred and heated for 7 hours in an oil bathat 150° C. After cooling, water was added. The product was extractedwith trichloromethane. The extract was dried, filtered and evaporated.The residue was crystallized from a mixture of 2-propanol and2,2'-oxybispropane. The product was filtered off and dried, yielding 2parts (60%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-phenoxypyridazine;mp. 123.4° C. (compound 264).

In a similar manner there were also prepared:

3-(4-chlorophenoxy)-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp.130.1° C. (compound 265); and

3-[4-(3-methylphenyl)-1-piperazinyl]-6-(phenylthio)pyridazine; mp.135.3° C. (compound 266).

Example 47

To a stirred solution of 0.7 parts of sodium in 20 parts ofbenzenemethanol were added 5.8 parts of3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole wasstirred and heated in an oil bath at 180° C. After standing overnight,water was added and the product was extracted with trichloromethane. Theextract was dried, filtered and evaporated. 2,2'-Oxybispropane was addedto the residue. The product was filtered off and crystallized from amixture of 2-propanol and methanol. The product was filtered off anddried, yielding 3.4 parts (47%) of3-[4-(3-methylphenyl)-1-piperazinyl]-6-(phenylmethoxy)pyridazine; mp.159.4° C. (compound 267).

In a similar manner there was also prepared:

4-(3-methylphenyl)-1-[6-(phenylmethoxy)-3-pyridazinyl]-4-piperidinol;mp. 124.8° C. (compound 268).

Example 48

A mixture of 6.1 parts of4-(3-methylphenyl)-1-[6-(phenylmethoxy)-3-pyridazinyl]-4-piperidinol and250 parts of 2-methoxyethanol was hydrogenated at normal pressure and atroom temperature with 2 parts of palladium-on-charcoal catalyst 10%.After the calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated. The residue was boiled in2-propanol. The product was filtered off and dried, yielding 4.5 parts(97%) of 6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol;mp. 264.6° C. (compound 269).

A mixture of 2.9 parts of6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol, 30 partsof a hydrochloric acid solution 6N and 24 parts of ethanol was stirredfor 2 hours at reflux temperature. The reaction mixture was evaporated.Crushed ice was added and the whole was treated with concentrateammonium hydroxide. The product was extracted with trichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of 2-propanol and 2,2'-oxybispropane. Theproduct was filtered off and dried, yielding 2 parts (75%) of6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)pyridinyl]-3-pyridazinol; mp.179.0° C. (compound 270).

Example 49

A mixture of 6 parts of3-[4-(3-methylphenyl)-1-piperazinyl]-6-(phenylmethoxy)pyridazine and 60parts of concentrate hydrochloric acid was stirred and refluxed for 3hours. The whole was allowed to stand overnight and treated withconcentrate ammonium hydroxide. The product was filtered off, washedwith water and dissolved in trichloromethane. The organic layer wasdried, filtered and evaporated. The residue was crystallized from amixture of 2-propanol and 2,2'-oxybispropane. The product was filteredoff and dried, yielding 4.5 parts (98%) of6-[4-(3-methylphenyl)-1-piperazinyl]-3(2H)-pyridazinone; mp. 209.8° C.(compound 271).

Example 50

A mixture of 7.3 parts of3-chloro-6-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine, 2 parts ofcalcium oxide and 200 parts of methanol was hydrogenated at normalpressure and at room temperature with 2 parts of palladium-on-charcoalcatalyst 10%. After the calculated amount of hydrogen was taken up, thecatalyst was filtered off over Hyflo and the filtrate was evaporated.The residue was crystallized from 2-propanol, yielding 4.1 parts (63.2%)of 3-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine; mp. 133.4° C.(compound 272).

Example 51

A mixture of 5.8 parts of3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 3 parts ofthiourea was stirred for 3 hours in an oil bath at 165° C. Aftercooling, there were added 150 parts of a sodium hydroxide solution 0.5N.The whole was stirred and refluxed for 15 minutes. It was filtered whilehot and the filtrate was neutralized with acetic acid. The product wasfiltered off, washed with water and separated by column chromatographyover silica gel using a mixture of trichloromethane and methanol(98.5:1.5 by volume) as eluent. The pure fractions were collected andthe eluent was evaporated. The residue was crystallized from a mixtureof ethanol and tetrahydrofuran. The product was filtered off and dried,yielding 1.3 parts (22.7%) of6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinethiol; mp. 174.2° C.(compound 273).

Example 52

To a stirred solution of 0.92 parts of sodium in 8 parts of methanolwere added 45 parts of benzene. Methanol was distilled off and then 6.2parts of methyl6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinecarboxylate and 3.5parts of ethyl acetate in 45 parts of benzene were added. The whole wasstirred and refluxed overnight. The reaction mixture was evaporated. 100Parts of water were added. The mixture was acidified with 24 parts ofconcentrate hydrochloric acid, boiled for 2 hours, cooled and treatedwith sodium hydrogen carbonate. The product was filtered off, washedwith water and dissolved in trichloromethane. The solution was dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (98:2 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized from amixture of 2-propanol and 2,2'-oxybispropane. The product was filteredoff and dried, yielding 3 parts (51%) of1-[6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinyl]ethanone; mp.135.9° C. (compound 274).

In a similar manner there were also prepared:

1-[6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-3-pyridazinyl]ethanone;mp. 115.0° C. (compound 275).

C. Pharmacological examples Example 53

In order to illustrate the useful anti-viral properties of the compoundsof the present invention a number of such compounds were tested in thepreviously described Rhinovirus Cythopatic Effect Test. These compoundstogether with the results of the test are gathered in the followingtable.

    ______________________________________                                                      lowest concentration                                            Compound No.  in μg/ml                                                     ______________________________________                                        5             10                                                              8             10                                                              29            0.4                                                             207           0.4                                                             149           0.4                                                             213           2                                                               34            0.08                                                            35            2                                                               36            0.4                                                             37            2                                                               40            0.016                                                           41            0.4                                                             44            0.4                                                             48            10                                                              10            2                                                               136           0.003                                                           26            0.4                                                             11            2                                                               25            2                                                               15            2                                                               16            10                                                              18            0.4                                                             21            2                                                               56            0.4                                                             57            2                                                               58            0.016                                                           257           10                                                              22            0.08                                                            24            2                                                               146           0.4                                                             23            0.016                                                           60            0.016                                                           61            0.08                                                            148           0.08                                                            63            0.016                                                           64            0.4                                                             203           0.003                                                           161           10                                                              66            2                                                               67            10                                                              69            0.4                                                             218           0.4                                                             165           0.08                                                            166           10                                                              77            0.08                                                            168           0.003                                                           170           2                                                               80            0.4                                                             204           0.003                                                           266           10                                                              83            2                                                               171           10                                                              202           0.016                                                           84            0.016                                                           172           2                                                               173           2                                                               258           0.0006                                                          142           0.016                                                           143           0.0006                                                          174           2                                                               86            10                                                              28            0.0006                                                          175           0.0006                                                          88            0.003                                                           89            0.4                                                             90            0.016                                                           91            0.4                                                             236           0.016                                                           93            0.08                                                            96            0.4                                                             238           2                                                               101           0.4                                                             104           2                                                               222           0.08                                                            223           0.08                                                            241           0.016                                                           145           0.003                                                           231           10                                                              112           0.08                                                            210           2                                                               113           10                                                              209           10                                                              247           0.4                                                             274           10                                                              120           2                                                               250           0.4                                                             273           0.08                                                            259           0.08                                                            126           2                                                               212           2                                                               275           2                                                               ______________________________________                                    

D. Composition Examples

"Active ingredient" (A.I.) as used throughout the following examplesrelates to a compound of formula (I), a possible stereochemicallyisomeric form or pharmaceutically acceptable acid addition salt thereof.

Example 54 Oral Drops

500 Grams of the A.I. was dissolved in 0.5 liters of 2-hydroxypropanoicacid and 1.5 liters of the polyethylene glycol at 60°-80° C. Aftercooling to 30°-40° C. there were added 35 liters of polyethylene glycoland the mixture was stirred well. Then there was added a solution of1750 grams of sodium saccharin in 2.5 liters of purified water and whilestirring there were added 2.5 liters of cocoa flavor and polyethyleneglycol q.s. to a volume of 50 liters, providing an oral drop solutioncomprising 10 milligrams of the A.I. per milliliter. The resultingsolution was filled into suitable containers.

Example 55 Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 liters of boiling purified water.In 3 liters of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 liters 1,2,3-propanetriol and 3 liters of sorbitol 70%solution were added thereto. 40 Grams of sodium saccharin were dissolvedin 0.5 liters of water and 2 milliliters of raspberry and 2 millilitersof gooseberry essence were added. The latter solution was combined withthe former, water was added q.s. to a volume of 20 liters providing anoral solution comprising 20 milligrams of the active ingredient perteaspoonful (5 milliliters). The resulting solution was filled insuitable containers.

Example 56 Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatingcapsules, comprising each 20 milligrams of the active ingredient.

Example 57 Film-Coated Tablets Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 milliliters of water. The wet powder mixture was sieved, dried andsieved again. Then there was added 100 grams microcrystalline celluloseand 15 grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10milligrams of the active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 milliliters ofdenaturated ethanol there was added a solution of 5 grams of ethylcellulose in 150 milliliters of dichloromethane. Then there were added75 milliliters of dichloromethane and 2.5 milliliters1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten anddissolved in 75 milliliters of dichloromethane. The latter solution wasadded to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 milliliters ofconcentrated colour suspension (Opaspray K-1-2109) and the whole washomogenated.

The tablet cores were coated with the thus obtained mixture in a coatingapparatus.

Example 58 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 liters of boiling waterfor injection. After cooling to about 50° C. there were added whilestirring 4 grams lactic acid, 0.05 propylene glycol and 4 grams of theA.I. The solution was cooled to room temperature and supplemented withwater for injection q.s. ad 1 liter volume, giving a solution of 4milligrams A.I. per milliliters. The solution was sterilized byfiltration (U.S.P. XVII p. 811) and filled in sterile containers.

Example 59 Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 milliliters polyethylene glycol 400.12 Grams surfactant and triglycerides q.s. ad 300 grams were moltentogether. The latter mixture was mixed well with the former solution.The thus obtained mixture was poured onto moulds at a temperature of37°-38° C. to form 100 suppositories each containing 30 milligrams ofthe active ingredient.

What is claimed is:
 1. A method of treating rhinoviral diseases inwarm-blooded animals suffering from said rhinoviral diseases, whichmethod comprises the systemic administration to warm-blooded animals ofan anti-rhinovirally effective amount of a compound of the formula:##STR194## a pharmaceutically acceptable acid-addition salt or astereoisomeric form or a tautomeric form thereof, wherein:R¹ is a memberselected from the group consisting of hydrogen, halo, 1H-imidazol-1-yl,lower alkyloxy, aryloxy, aryllower alkyloxy, lower alkylthio, arylthio,hydroxy, mercapto, amino, lower alkylsulfinyl, lower alkylsulfonyl,cyano, lower alkyloxycarbonyl, lower alkylcarbonyl, and lower alkyl; R²and R³ are, each independently, members selected from the groupconsisting of hydrogen and lower alkyl, or R² and R³ combined may form abivalent radical of formula --CH═CH--CH═CH--, provided that when R² is abranched chain alkyl then neither R¹ nor R³ can be a branched chainalkyl; and A is a bivalent radical of the formula:

    --C.sub.m H.sub.2m --C(R.sup.5)(R.sup.6)--C.sub.n H.sub.2n --(c); or

    --C.sub.m-1 H.sub.2(m-1) --C(R.sup.7)═C(R.sup.8)--C.sub.n H.sub.2n --(d);

wherein one of the hydrogen atoms within the radical C_(m) H_(2m),C_(m-1) H₂(m-1), or C_(n) H_(2n) may be replaced by lower alkyl or aryl;m and n are, each independently, integers of from 1 to 4, inclusive, thesum of m and n being 3, 4, or 5; R⁵ is hydrogen; lower alkyl; aryl;hydroxy; lower alkyloxy; aryloxy; lower alkyloxy being substituted withmorpholine, pyrrolidine, or piperidine; amino; (loweralkyloxycarbonyl)amino; arylamino; (aryl) (lower alkyl)amino; (arylloweralkyl)amino; (aryllower alkenyl)amino; (aryllower alkenyl) (loweralkyl)amino; or arylcarbonyloxy; R⁶ is hydrogen; aryl; lower alkyl;(lower alkylcarbonyl amino)lower alkyl, aryllower alkyl;arylcarbonyllower alkyl; aminocarbonyl; arylcarbonyl; arylaminocarbonyl;(arylloweralkyl)carbonyl, lower alkyloxycarbonyl; indolyl; or pyridinyl;and R⁷ and R⁸ are, each independently, members selected from the groupconsisting of hydrogen, lower alkyl, aryl, aryllower alkyl, andpyridinyl; wherein aryl is phenyl, being optionally substituted with upto 3 substituents, each independently selected from the group consistingof halo, lower alkyl, trifluoromethyl, nitro, amino, lower alkyloxy,hydroxy and lower alkyloxycarbonyl; thienyl; and naphthalenyl.
 2. Amethod according to claim 1, wherein: ##STR195## is other thanpiperidinyl when R¹ is hydrogen and R² and R³ combined form a bivalent--CH═CH--CH═CH-- radical; and ##STR196## is other than piperidinyl andhexahydro-1H-azepinyl when R¹ is halo, R² is lower alkyl, and R³ ishydrogen.
 3. A method according to claim 1, wherein A is a bivalentradical of formula (c) wherein R⁵ is hydrogen, aryl, arylamino,(aryl)(loweralkyl)amino, hydroxy, or indolyl, and R⁶ is hydrogen, aryl,arylcarbonyl, or (arylcarbonyl)lower alkyl, or wherein A is a bivalentradical of formula (d).
 4. A method according to claim 3, wherein R² andR³ are both hydrogen.
 5. A method according to claim 4, wherein in theradical A having the formula (c) m is the integer 1 or 2 and n is theinteger 2, and in the radical A of formula (d), m is the integer 1 or 2and n is the integer
 2. 6. A method according to claim 5, wherein R¹ ishalo, lower alkyloxy, aryloxy, lower alkylthio, arylthio, or cyano.
 7. Amethod according to claim 5, wherein R¹ is halo.
 8. A method accordingto claim 1, wherein the compound is3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine.9. A method according to claim 1, wherein A is a bivalent radical offormula (c) provided that when R⁶ is hydrogen, then R⁵ is other thanhydrogen, hydroxy or lower alkyl.